RESEARCH PROJECT 2- PROJECT SUMMARY The goal of this MUSC TCC project is to develop more precise biomarkers of prostate cancer initiation and progression, and determine how to treat and manage prostate cancer among minority men within the context of their biological risk for poor outcomes and social, psychological, and physiological (i.e., allostatic load/AL) stressors. This will be done using several new innovative experimental approaches directly on archived tissues unique to MUSC, using a rich resource cohort of samples (n=570) representing approximately one third African American (AA) subjects. Based on the epidemiology of prostate cancer among AA men (already described in the proposal), considerable efforts have been made to promote early detection through screening with prostate specific antigen (PSA) testing. Recently, however, screening guidelines have shifted from performance of annual screening starting at age 50 to informed decision-making as new data have emerged about the efficacy of PSA testing. As early detection plays a less prominent role in prostate cancer control, it becomes even more important to identify biological pathways that are activated in the initiation and progression of disease and develop more effective biomarkers for early detection. Several prior studies have shown that there is a complex interplay between the tumor microenvironment and the immune system that contributes to the development of more aggressive prostate cancer among AA men. However, biological processes related to immune functioning operate within and are influenced by social contextual factors. Thus, identifying biological mechanisms without understanding the ways in which they are associated with social determinants is necessary, but not sufficient to long-term efforts to reduce racial disparities in prostate cancer outcomes through early detection and clinical management of disease. An emerging hypothesis central to this application about cancer health disparities is that social conditions and psychological responses to social stressors influence biological processes that are important to the initiation and progression of cancer. In this project, MUSC investigators will examine this hypothesis through a transdisciplinary study that defines the molecular mechanisms involved in the initiation and progression of prostate cancer by evaluating the tumor microenvironment interactions between the immune system, the tumor glycome, social determinants and AL. These investigators will determine whether the combination of distinct tumor and stroma N-glycans in prostate cancers of AA men promotes a more pro-tumor inflammatory/immune microenvironment. They will also examine the relationship between these biological processes and social determinants that include isolation, perceived stress, and chronic socioeconomic stressors. They hypothesize that a combination of stress- inducing social determinants, distinct N-glycans, impaired immune/inflammatory balance contributes to more aggressive prostate cancers in the AA population.